Monoclonal antibody (mAb) treatment of organ transplant recipients has been a major development in the treatment of allograft rejection. The advantages of mAbs include their known specificity, consistent biological activity, and ease of administration. Of all mAbs clinically and experimentally tested in man, the most efficacious is the OKT3 mAb which recognizes the T cells receptor (TCR) complex on the surface of alloreactive cells. However, several limitations to the use of the OKT3 reagent persists. These include the significant adverse reactions following the initial dose, production by the recipient of antibodies to the OKT3 antibody, and the broad but transient nature of the induced immunosuppression. Our laboratory has recently developed an anti-murine CD3 mAb that reacts with all mouse T cells expressing a TCR complex. Initial studies in the laboratory suggest that treatment with the mAb in vivo has profound long term immunosuppressive effects including prolonged skin graft survival and depressed cellular immunity. Although the initial immunosuppression is a consequence of T cell depletion and receptor blockade, T cells that survive treatment continue to be hyporesponsive. Thus, this hamster mAb provides the first anti-CD3 that can be used in a well-defined small animal model to provide a systematic evaluation of the use of anti-CD3 in vivo to suppress transplantation responses. Since anti-CD3 suppresses the immune response by affecting all T cells, the potential for generalized immunosuppression and susceptibility to opportunistic infections remains a great risk. Therefore, efforts will be designed to focus immunosuppression specifically on T cell subsets critical in allorecognition. Thus, subset-specific, mAbs and other T cell reagents will be used to suppress individual V(beta) expressing T cells which predominate in allorecognition. In addition, anti-CD3 will be coupled to anti-CD4 and anti-CD8 to suppress these subsets of T cells. Thus, the more specific mAb treatment should lead to a more sophisticated immunosuppressive regimen that selectively alters immunity towards the organ transplant.